rs11855415

chr15-101334918-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002570.5(PCSK6):c.1859-2887T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 152,016 control chromosomes in the GnomAD database, including 48,369 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (48369 hom., cov: 30)
• Consequence: PCSK6 NM_002570.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0930

Genes affected

PCSK6 (HGNC:8569): (proprotein convertase subtilisin/kexin type 6) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an initial autocatalytic processing event in the ER to generate a heterodimer which exits the ER and sorts to the trans-Golgi network where a second autocatalytic event takes place and the catalytic activity is acquired. The encoded protease is constitutively secreted into the extracellular matrix and expressed in many tissues, including neuroendocrine, liver, gut, and brain. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. This gene is thought to play a role in tumor progression and left-right patterning. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Feb 2014]

PCSK6-AS1 (HGNC:51448): (PCSK6 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK6	NM_002570.5	c.1859-2887T>A		intron_variant		ENST00000611716.5
PCSK6-AS1	NR_132373.1	n.77+405A>T		intron_variant, non_coding_transcript_variant
PCSK6	NM_001291309.2	c.1637-2887T>A		intron_variant
PCSK6	NM_138319.4	c.1859-2887T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK6	ENST00000611716.5	c.1859-2887T>A		intron_variant		1	NM_002570.5	A2
PCSK6-AS1	ENST00000558696.1	n.77+405A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120911 AN: 151898 Hom.: 48328 Cov.: 30

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.761

Gnomad NFE AF: 0.779

Gnomad OTH AF: 0.790

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.796 AC: 121008 AN: 152016 Hom.: 48369 Cov.: 30 AF XY: 0.791 AC XY: 58770 AN XY: 74270

Gnomad4 AFR AF: 0.851

Gnomad4 AMR AF: 0.831

Gnomad4 ASJ AF: 0.689

Gnomad4 EAS AF: 0.789

Gnomad4 SAS AF: 0.587

Gnomad4 FIN AF: 0.770

Gnomad4 NFE AF: 0.779

Gnomad4 OTH AF: 0.788

Alfa AF: 0.785 Hom.: 5837

Bravo AF: 0.812

Asia WGS AF: 0.702 AC: 2441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	6.3
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11855415; hg19: chr15-101875123;